Illicit drug use is a highly prevalent problem associated with a number of costly social and economic consequences including increased unemployment, homelessness, crime, and transmission of STDs including HIV. Given the costly and pervasive nature of illicit substance use, researchers have focused on mechanisms underlying substance use and relapse to identify targets for prevention and treatment. One biopsychological mechanism of interest is the biological stress response system: the hypothalamic-pituitary-adrenal (HPA) axis and its primary hormone, cortisol. Neurobiological models of addiction suggest that chronic substance use is associated with a deviation of the HPA axis from its normal state of functioning, which is hypothesized to contribute to a reduced ability to adapt or cope with additional stressors, thereby increasing one's risk of stress-induced relapse. A number of empirical studies in human cocaine and stimulant addicts have provided support for HPA dysregulation in chronic cocaine users, and findings suggest that this dysregulation is associated with deleterious substance use outcomes. However, existing studies are limited and key information regarding the true nature of HPA axis functioning in chronic cocaine users remains to be elucidated. Specifically, it is unclear to what extent previous findings have been confounded by the effects of acute nicotine exposure immediately prior to testing. Additionally, differences in stress induced HPA axis functioning between cocaine users and non-drug users remains unclear because few studies to date have included a comparison group of healthy non-drug users. A greater understanding of this biological mechanism is crucial in order to develop and examine pharmacological interventions for human cocaine users that specifically target HPA axis dysfunction. Thus, the current study aims to extend the literature in our understanding of how cocaine use is associated with a dysfunctional HPA axis response to psychological stress, separate from the effects of chronic and acute nicotine use. To do this, we will recruit non-smoking cocaine dependent individuals, and healthy, non-substance using control participants (also nonsmoking), and assess HPA axis reactivity to psychological stress in both samples, as measured by salivary cortisol concentrations. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a chronically relapsing disorder that poses a significant public health risk, as it is associated with costly social and economic consequences. By isolating and examining the role of biological vulnerabilities underlying cocaine use, such as HPA axis dysfunction, researchers may better understand basic processes that may serve as targets for future behavioral and pharmacological treatments aimed to improve substance use outcomes. As such, the current study aims to replicate and extend previous studies by examining HPA axis reactivity to stress among a sample of non-smoking cocaine users and healthy (also non- smoking) non-substance users in order to better understand the relationship between chronic cocaine use and HPA axis dysfunction.